While transforming growth factor- (TGF-) has a dual tumor suppressor/tumor promoter role in tumorigenesis, the role of other TGF- superfamily ligands, including the bone morphogenetic proteins (BMPs), is just being defined. TGF- superfamily ligands utilize a signaling coreceptor, the type III TGF- receptor (TRIII), to mediate and regulate ligand binding and signaling through the type I and type II TGF- superfamily receptors. TRIII also undergoes ectodomain shedding to produce a natural soluble form of TRIII (sTRIII), which we have detected in human plasma. We have recently established that TRIII also functions as a BMP co-receptor and is required for some BMP-mediated biology, and that TRIII and BMP have roles in pancreatic cancer EMT and progression. To investigate the mechanism of TRIII function in human pancreatic cancer the following hypothesis is proposed: BMPs have dichotomous effects on pancreatic cancer progression, with loss of autocrine BMP responsiveness, in part through loss of TRIII expression and decreased ALK-6 signaling, facilitating cancer initiation and elevated BMP levels, in part through loss of sTRIII expression, then promoting cancer progression through EMT-mediated increases in cellular motility and invasiveness. This hypothesis will be addressed by four Specific Aims. Specific Aim1: The mechanism by which TRIII orchestrates the relative bioactivity of TGF- superfamily ligands in pancreatic cancer will be explored by defining the structural determinants mediating TRIII ligand binding to BMP, determining the relative ligand binding hierarchy of TGF- superfamily ligands to TRIII and sTRIII, establishing whether sTRIII serves as an antagonist of BMP signaling and whether the relative expression of TRIII and sTRIII regulate the cellular effects of TGF- superfamily ligands in pancreatic cancer cells. Specific Aim2: The mechanism by which TRIII selectively increases BMP signaling through ALK-6 will be established by defining whether TRIII selectively mediates the interaction of ALK-6 with -arrestin2 to selectively mediate the internalization of ALK-6 and establishing whether TRIII mediated ALK-3/ALK-6 internalization is necessary for BMP signaling and BMP-mediated biology. Specific Aim3: The levels of cell surface TRIII, circulating sTRIII and circulating active TGF- superfamily members will be established in murine models and human specimens to establish whether these levels are coordinately regulated during pancreatic cancer progression. Specific Aim4: The effect of increasing or decreasing TRIII and/or sTRIII expression in murine pancreatic cancer models of initiation and progression will be established to define whether TRIII and/or sTRIII have opposing effects on pancreatic cancer initiation and progression. These studies will define the mechanism by which TRIII orchestrates TGF- superfamily signaling to regulate the initiation and progression of pancreatic cancer, define the biological implications of TRIII ectodomain shedding in the context of pancreatic cancer and aid in targeting these pathways for the prevention and treatment of human cancers.